Summary: Age-related macular degeneration (AMD) is a leading cause of vision loss world-wide among people over 59. It accounts for approximately 50% of the blindness in the Western world. AMD stems from the age-related degeneration of retinal pigment epithelium (RPE) and the photoreceptors in the macular area of the retina. The underlying mechanism of this disease is unclear; there are no effective preventive strategies or treatments. Recent studies suggest that oxidative stress is involved in the etiology of AMD, and that damage to RPE increases with age. We hypothesize that damage to RPE mitochondria caused by oxidative stress contributes to the retinal degeneration observed in AMD and that compounds such as alpha-lipoic acid, coenzyme Q10, and acetyl-L-carnitine, which protect mitochondria against oxidative insult, may prevent or lessen oxidant induced RPE cellular damage. Different mitochondrial nutrients exert their protective effects via different pathways; thus, combinations of these compounds may have additive or synergistic effects. [unreadable] We propose to identify the combinations of these mitochondrial nutrients that are most effective in preventing and treating oxidant-induced mitochondrial damage. The proposed experiments, using confluent monolayers of human fetal RPE, can be summarized in four Specific Aims: (1) Determine the protective effects of mitochondrial nutrients, both individually and in optimal combinations, when administered prior to oxidative stress in RPE ("pretreatment"). (2) Identify the pathways involved in oxidant-induced mitochondrial damage following pretreatment; (3) Determine the therapeutic effects of mitochondrial nutrients, both individually and in optimal combinations, when administered following acute and chronic oxidant-induced mitochondrial damage in RPE ("post-treatment"). (4) Identify the pathways involved in oxidant-induced mitochondrial damage during post-treatment. This in vitro analysis of mitochondrial nutrients may provide the basis for the development of therapeutic agents that can prevent and/or reduce the retinal and RPE pathophysiology observed in AMD. [unreadable] [unreadable] [unreadable]